The present invention relates to processes for the preparation of novel substituted propenone derivatives and their crystals, in detail processes for the preparation of their intermediates, 2-acyl-5-benzylfuran derivatives and 1,2,4-triazole-3-carboxylic acid ester derivatives.
2-Acyl-5-alkylfuran derivatives, which are similar to 2-acyl-5-benzylfuran derivatives, can be prepared by introducing an acyl group to 2-alkyfuran derivatives through Friedel Crafts reaction (Japanese Patent Publication (Kokoku) 1995-78056, Japanese Patent Publication (Kokoku) 1995-78056 and Japanese Patent Publication (Kokai) 1986-53275).
2-Alkylfuran derivatives can be prepared by introducing an alkyl group to furan derivatives through Priedel Crafts reaction (Chem. France. 1962, 1166).
However, the preparation of 2-acyl-5-benzylfuran derivatives is not disclosed in these documents.
On the other hand, it is known that 1,2,4-triazole-3-carboxylic acid can be prepared by converting an amino group of 3-amino-1,2,4-triazole-5-carboxylic acid to a diazo group, isolating the diazonium salt and reducing.
It is known as a reducing method that 1) a diazonium salt is reduced with sodium hypophosphite (NaH2PO2) and concentrated hydrochloric acid (HCl) under 15xc2x0 C. (Khim. Geterotsikl. Soedin., 1967, 180-183) and 2) a diazonium salt is reduced at 45 to 50xc2x0 C. in methanol (Khim. Geterotsikl. Soedin., 1965, 624-626).
In is known as a deaminating method of 3-amino-1,2,4-triazole that diazonation and reduction are carried out at the same time (J. Am. Chem. Soc. 76, 290, 1954).
As another process, 1,2,4-triazole-3-carboxylic acid ester can be prepared by heating acylamidrazone over its melting point (150 to 200xc2x0 C.) to cyclize (Collect. Czech. Chem. Commun., 49, 1984, 2492-2495, J. Heterocyclic Chem., 25, 651-654, 1998). The document describes that a large scale of cyclization must be preformed under reduced pressure with heating over its melting point for removing the generated water.
A compound of the formula (VI-1): 
wherein R1, R2 and R4 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; A is CR6 or N; and R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl, has an anti-HIV activity by inhibiting HIV integrase.
A compound of the formula (VI-1) can be prepared in the following method. 
wherein R1, R2, R4 and A are as defined above; Q is a protecting group; and L is a leaving group.
Industrial and commercial preparations of 2acyl-5-benzylfuran derivatives and 1,2,4-triazole-3-carboxylic acid ester derivatives, which are useful intermediates of the compound (VI-1), are desired.
First, the preparation of 2-acyl-5-benzylfuran derivatives is described below.
As a conventional route, for example, the following methods can be thought.

wherein any ring may be substituted with optionally substituted alkyl, optionally substituted alkoxy and/or halogen.
In method X, 2-furoic acid, a starting material is reacted with benzaldehyde. After removing the hydroxy group from the obtained compound, the carboxy group is esterified to give 2-pyridine thioester, which is reacted with methyl magnesium bromide to give 2-acetyl-5-benzylfuran. This method requires 2-pyridine thioester which is removed at the following step for converting the carboxy group to acetyl.
In method Y, furfural, a starting material, is reacted with phenyl magnesium bromide. After removing the hydroxy group of the obtained compound, 2-acetyl-5-benzylfuran is prepared through Friedel Crafts reaction. The final step of this method requires Friedel Crafts reaction which must be carried out under acidic condition. However, 2-benzylfuran is unstable under acidic condition, so 2-acyl-5-benzylfuran can not be prepared in high yield.
Since both of methods X and Y require many steps and many reagents, 2-acetyl-5-benzylfuran derivatives can not be industrially and commercially prepared.
The present inventors have solved the above problems on methods X and Y, and found out industrial and commercial processes for the preparation of 2-acyl-5-benzylfuran derivatives can be achieved through Friedel Crafts reaction of 2-acylfuran derivatives.
The present inventions of 2-acsyfuran derivatives include;
A-1) a process for the preparation of a compound of the formula (III-1): 
wherein R1 and R2 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; R3 is optionally substituted alkyl or optionally substituted alkoxy; and R4 is hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen, which comprises reacting a compound of the formula (I-1): 
wherein R1, R2 and R3 each is as defined above,
with a compound of the formula (II-1): 
wherein R4 is as defined above; and X is halogen,
in the presence of a Lewis acid,
A-2) the process according to the above A-1) wherein a reaction solvent is methylene chloride,
A-3) the process according to the above A-1) wherein a reaction solvent is water,
A-4) the process according to any one of the above A-1) to A-3) wherein R3 is methyl,
A-5) the process according to any one of the above A-1) to A-4) wherein R1 and R2 each is hydrogen, and
A-6) the process according to any one of the above A-1) to A-5) wherein R4 is 4-fluoro.
Second, the preparation of 1,2,4-triazole-3-carboxylic acid ester derivatives is described below.
A conventional process for the preparation of 1,2,4-triazole-3-carboxlic acid comprising a reduction of an isolated diazonium salt is accompanied with danger of explosion when a large amount of a diazonium salt is treated, so this process is not suitable to industrial production.
A process for the preparation of 1,2,4-triazole-3-carboxilic acid ester comprising a cyclization of acylamidrazone requires heating over a melting point, so this process is not suitable in an industrial scale, too.
Then, the present inventors have solved the above problems and found out processes for the preparation of 1,2,4-triazole-3-carboxilic acid ester derivatives as shown below, which are suitable in an industrial scale.
The present inventions of 1,2,4-triazole-3-carboxilic acid ester derivatives include;
B-1) a process for the preparation of a compound of the formula (IV-2): 
wherein R5 is hydrogen or optionally substituted alkyl,
which comprises reacting a compound of the formula (IV-1): 
wherein R5 is as defined above,
with an alkaline metal nitrite or an alkaline-earth metal nitrite in the presence of a reducing agent,
B-2) the process according to the above B-1) which comprises reacting a compound of the formula (IV-1) with an alkaline metal nitrite in the presence of hypophosphorous acid as the reducing agent,
B-3) the process according to the above B-1) or B-2) which is carried out under the addition of a small amount of alchol,
B-4) the process according to any one of the above B-1) to B-3) wherein R5 is hydrogen,
B-5) a process for the preparation of a compound of the formula (IV-3): 
wherein R5 is optionally substituted alkyl,
which comprises preparing 1,2,4-triazole-3-carboxilic acid through the process according to the above B-4) and esterifing the obtained compound,
B-6) a process for a compound of the formula (IV-43): 
wherein R5 is hydrogen or optionally substituted alkyl; and R6 is hydrogen,
optionally substituted alkyl or optionally substituted aryl,
which comprises cyclizing a compound of the formula (V): 
wherein R5 and R6 are as defined above,
in the presence of trialkylorthoester or a catalytic amount of an acid,
B-7) the process according to the above B-6) wherein R5 is optionally substituted alkyl,
B-8) the process according to the above B-6) wherein R5 is optionally substituted alkyl; and R6 is hydrogen,
B-9) a process for the preparation of a compound of the formula (IV-6): 
wherein R5 is optionally substituted alkyl; R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl; and R12 is a group of the formula: xe2x80x94R7 wherein R7 is trityl, optionally substituted sulfamoyl or optionally substituted alkoxymethyl, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8 is optionally substituted alkyl; R9, R10 and R11 each is independently hydrogen or optionally substituted alkyl; or R5 and R10 may be taken together to form optionally substituted alkylene, or hydroxymethyl, which comprises preparing a compound of the formula (IV-5): 
wherein R5 and R6 are as defined above, through the process according to any one of the above B-1) to B-3) and B-5) to B-8), and reacting the obtained compound with a compound of the formula: R7X wherein R7 is as defined above; and X is halogen, a compound of the formula: (R8O)R9Cxe2x95x90CR10R11 wherein R8, R9, R10 and R11 are as defined above, or formaldehyde,
B-10) a process of the preparation of a compound of the formula (IV-8): 
wherein R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl; and R12 is a group of the formula: xe2x80x94R7 wherein R7 is trityl, optionally substituted sulfamoyl or optionally substituted alkoxymethyl, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8 is optionally substituted alkyl; R9, R10 and R11 each is independently hydrogen or optionally substituted alkyl, or R8 and R10 may be taken together to form optionally substituted alkylene, or hydroxymethyl, which comprises preparing a compound of the formula:(IV-7): 
wherein R6 is as defined above, through the process according to the above B-4) or B-6), and reacting the obtained compound with a compound of the formula: R7X wherein R7 is as defined above; and X is halogen, a compound of the formula: (R8O)R9Cxe2x95x90CR10R11 wherein R8, R9, R10 and R11 are as defined above, or formaldehyde,
B-11) the process according to the above B-9) or B-10) which comprises reacting a compound of the formula (IV-7) with a compound of the formula: R7X wherein R7 is trityl,
B-12) the process according to the above B-9) or B-10) which comprises reacting a compound of the formula (IV-7) with a compound of the formula: (R8O)R9Cxe2x95x90CR10R11 wherein R5 and R10 are taken together to form trimethylene; and R9 and R11 a hihydrogen,
B-13) the process according to the above B-9) or B-10) which comprises reacting a compound of the formula (IV-7) with a compound of the formula: (R8O)R9Cxe2x95x90CR10R11 wherein R8 and R9 each is methyl; and R10 and R11 each is hydrogen,
B-14) a compound of the formula (IV-9): 
wherein R6 is hydrogen or alkyl; R13 is alkyl, a group of the formula: xe2x80x94R7 wherein R7 is trityl, optionally substituted sulfamoyl or alkoxymethyl, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8 is alkyl; R9, R10 and R11 each is independently hydrogen or alkyl; or R8 and R10 may be taken together to form alkylene, or hydroxymethyl; and R14 is a group of the formula: xe2x80x94R7 wherein R7 is as defined above, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8, R9, R10 and R11 are defined above, or hydroxymethyl, provided that a compound wherein R6 is hydrogen; R13 is methyl; and R14 is trityl, a compound wherein R6 is hydrogen; R13 is methyl; and R14 is tetrahydropyran-2-yl, and a compound wherein R6 is hydrogen; R13 is ethyl; and R14 is trityl are excluded,
B-15) the compound according to the above B-14) wherein R6 is hydrogen;
R13 is methyl or ethyl; and R14 is tetrahydropyran-2-yl, hydroxymethyl, methoxymethyl, ethoxymethyl, N,N-dimethylsulfamoyl, (1-methoxy-1-methyl)ethyl, (1-ethoxy)ethyl, (1ethoxy-1-methyl)ethyl, (1-n-propoxy)ethyl, (1-n-butoxy)ethyl or (1-isobutoxy)ethyl.
The present inventions for the preparation of substituted propenone derivatives accompanied by the above A) and/or B) include;
C-1) a process for the preparation of a compound of the formula (VI-1): 
wherein R1, R2 and R4 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; A is CR6 or NA; and R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl, which comprises preparing a compound of the formula (III-2): 
wherein R1, R2 and R4 are as defined above, through the process according to the above A-4), reacting the compound of the formula (III-2) with a compound of the formula (IV-10): 
wherein A is as defined above, Q is a protecting group; and L is a leaving group, in the presence of a base, and deprotecting Q,
C-2) the process according to the above C-1) wherein R1 and R2 each is hydrogen; and R4 is halogen,
C-3) the process according to the above C-1) or C-2) wherein R4 is 4-fluoro,
C-4) the process according to any one of the above C-1) to C-3) wherein A is CH,
C-5) a process for the preparation of a compound of the formula (IV-2): 
wherein R1, R2 and R4 each is independently hydrogen, optionally substituted, alkyl, optionally substituted alkoxy or halogen; and R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl, which comprises preparing a compound of the formula (IV-11): 
wherein R6 is as defined above, R13 is optionally substituted alkyl, a group of the formula: xe2x80x94R7 wherein R7 is trityl, optionally substituted sulfamoyl or, optionally substituted alkoxymethyl, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8 is alkyl; R9, R10 and R11 each is independently hydrogen or optionally substituted alkyl; or R8 and R10 may be taken together to form alkylene, or hydroxymethyl; and R14 is a group of the formula: xe2x80x94R7 wherein R7 is as defined above, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8, R9, R10 and R11 are defined above, or hydroxymethyl, through the process according to the above B-9) or B-10), reacting the obtained compound with a compound of the formula (III-2): 
wherein R1, R2 and R4 are as defined above, and deprotecting R14,
C-6) the process according to the above C-5) which comprises preparing the compound of the formula (III-2): 
wherein R1, R2 and R4 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen through the process according to the above A-4),
C-7) the process according to the above C-5) or C-6) wherein R1, R2 and R6 each is hydrogen; and R4 is halogen,
C-8) a compound of the formula (VI-7): 
wherein R1, R2 and R4 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; R6 is hydrogen, optionally, substituted alkyl or optionally substituted aryl; and R14 is a group of the formula: xe2x80x94R7 wherein R7 is trityl, optionally substituted sulfamoyl or optionally substituted alkoxymethyl, a group of the formula: xe2x80x94C(OR8)R9xe2x80x94CHR10R11 wherein R8 is alkyl; R9, R10 and R11 each is independently hydrogen or optionally substituted alkyl; or R8 and R10 may be taken together to form alkylene, or hydroxymethyl, and
C-9) the compound according to the above C-8) wherein R4 is 4-fluoro; R1, R2 and R6 each is hydrogen; and R14 is trityl, tetrahydropyran-2-yl, hydroxymethyl, methoxymethyl, ethoxymethyl, N,N-dimethylsulfamoyl, (1-methoxy-1-methyl)ethyl, (1-ethoxy)ethyl, (1-ethoxy-1-methyl)ethyl, (1-n-propoxy)ethyl, (1-n-butoxy)ethyl or (1-isobutoxy)ethyl.
The present inventions for a crystal of the above novel substituted propenone derivative include;
D-1) a crystal of an isomer having a chemical structure of the formula (VI-1): 
wherein A is CR6 or N; R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl; and R1, R2 and R4 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen, D-2) the crystal according to the above D-1) wherein R1 and R2 each is hydrogen; R4 is p-fluoro; and A is CH,
D-3) the crystal according to the above D-2) of which crystal parameters by single crystal X-ray diffraction are unit cell constants a=32.432(2) xc3x85, b=10.886(2) xc3x85, c=7.960(2) xc3x85, xcex1=90.00xc2x0, xcex2=90.00xc2x0, xcex3=90.00xc2x0, V=2810(1) xc3x853, Z=8; a space group Pbca; and density of 1.481 g/cm3,
D-4) the crystal according to the above D-2) of which diffraction angles (2xcex8) of main peaks by powder X-ray diffraction are 20.380, 21.280, 21.340, 23.140, 23.360, 23.540, 25.860, 27.460, 27.500, 28.100, 28.180, 29.400 and 29.480 (degree),
D-5) a crystal of an isomer having a chemical structure of the formula (VI-4): 
wherein A is CR6 or N; R8 is hydrogen, optionally substituted alkyl or optionally substituted aryl; and R1, R2 and R4 each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen,
D-6) the crystal according to the above D-5) wherein R1 and R2 each is hydrogen; R4 is p-fluoro; and A is CH,
D-7) the crystal according to the above D-6) of which crystal parameters by single crystal X-ray diffraction are unit cell constants a=11.9003(7) xc3x85, b=9.7183(5) xc3x85, c=13.2617(8) xc3x85, xcex1=90.00xc2x0, xcex2=109.450(4)xc2x0, xcex3=90.00xc2x0, V=1446.2(1) xc3x853 and Z=4; a space group P21/n; and density of 1.439 g/cm3,
D-8) the crystal according to the above D-6) of which diffraction angles (2xcex8) of main peaks by powder X-ray diffraction are 8.760, 19.600, 22.080, 23.760, 26.200, 27.580 and 29.080 (degree), and
D-9) a crystal of an isomer of 1-[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-triazole-3-yl)propenone of which diffraction angles (2xcex8) of main peaks by powder X-ray diffraction are 10.520, 13.860, 15.680, 18.160, 22.840, 26.180 and 28.120 (degree).
Each term to be used in the present specification is explained below.
The term xe2x80x9calkylxe2x80x9d includes C1 to C6 straight or branched alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or the like. Preferred is methyl or ethyl.
The term xe2x80x9calkylenexe2x80x9d includes C2 to C6 straight or branched alkylene, for example, ethylene, propylene, trimethylene, ethylethylene, tetramethylene or the like. Preferred is trimethylene.
The term xe2x80x9calkoxyxe2x80x9d includes C1 to C6 straight or branched alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy or the like. Preferred is methoxy or ethoxy.
The term xe2x80x9calkoxymethylxe2x80x9d includes methyl group substituted with the above alkyloxy, for example, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, n-pentyloxymethyl, isopentyloxymethyl, neopentyloxymethyl, tert-pentyloxymetbyl, n-hexyloxymethyl, isohexyloxymethyl or the like. Preferred is methoxy or ethoxymethyl.
The term xe2x80x9carylxe2x80x9d includes C6 to C14 aromatic carbocycle, for example, phenyl, naphthyl, anthryl, phenanthryl or the like. Preferred is phenyl.
The term xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo or iodo. Preferred in X is chloro or bromo. Preferred in R13 is fluoro, especially para-substituted fluoro.
The term xe2x80x9ctritylxe2x80x9d means a group of the formula: xe2x80x94CPh3 wherein Ph is phenyl.
The term xe2x80x9coptionally substituted sulfamoylxe2x80x9d includes unsubstituted sulfamoyl and sulfamoyl mono- or di-substituted with alkyl, for, example, sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-ethylsulfamoyl, N,N-diethylsulfamoyl or the like.
The substituents of xe2x80x9coptionally substituted alkylxe2x80x9d, xe2x80x9coptionally substituted alkoxymethylxe2x80x9d and xe2x80x9coptionally substituted alkylenexe2x80x9d include aryl. (e.g., phenyl or the like), cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl or the like), cyano, nitro, hydroxy, amino, halogenated alkyl (e.g., trifluoromethyl or the like) or the like.
The substituents of xe2x80x9coptionally substituted arylxe2x80x9d include alkyl (e.g, methyl, ethyl or the like), alkenyl (e.g., vinyl, allyl or the like), halogen, hydroxy, alkoxy (e.g., methoxy, ethoxy or the like), halogenated alkyl (e.g., trifluoromethyl or the like), nitro, sulfamoyl, amino, alkyl-substituted amino (e.g., methylamino, dimethylamino or the like), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl or the like), cyano or the like.